Medicines in pregnancy – safe?

Published in Health News and Evidence

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Practice points | Is safe a relative term? | Pitfalls of prescribing in pregnancy | Realistic guidance | Sources of further information | References


A recent article in JAMA Pediatrics has once again questioned the use of medicines in pregnancy. Since the thalidomide experience, medicine use in pregnant women has generally been viewed as risky and potentially harmful to the developing fetus. Is this fear justified?

There are medicines that are acknowledged to be harmful to the developing fetus, however, many medicines used today have little evidence of harm. Indeed, untreated maternal illness may cause more significant harm and requires careful consideration.

Optimal medicine use in pregnancy is vital for the health of mothers and babies. Here we explore some of the complexities around prescribing in pregnancy and ask: is safe a relative term?

Practice points

  • Balance risk and benefits of prescribing medicines in pregnancy
    While some medicines may have the potential to harm the unborn baby, not treating an illness or medical condition during pregnancy may also have negative consequences.
  • Take care when discussing risk with pregnant patients
    Overly cautious advice may have negative consequences including suboptimal treatment or the cessation of necessary medicines.
  • Information sources may not always provide the right context for an individual’s situation
    The TGA prescribing in pregnancy database provides information on the available safety data for a medicine but is not intended to replace medical advice.
    Check other sources for information on teratogenicity such as pregnancy drug information services in your State or Territory.
  • Follow rational prescribing guidelines in pregnancy such as those from Therapeutic Guidelines or the Australian Medicines Handbook
    Consider non-pharmacological treatment where available.
    Assess the harms of a particular medicine and balance these against the harms of not treating a condition.

Medicine use in pregnancy: is safe a relative term?

Most women take medicines – prescription, over-the-counter or complementary –while pregnant.1,2 A recent article published in JAMA Pediatrics associated using paracetamol in pregnancy with ADHD.3 While the JAMA study did not confirm a causative link between paracetamol exposure and ADHD, (See Behind the headlines: ADHD linked to paracetamol use during pregnancy) it has once again raised the question of how to determine which medicines are safe during pregnancy. Should any medicine be considered safe in pregnancy?

Balancing the risks

Prescribing in pregnancy is a balancing act between protecting the mother from the harms associated with untreated medical conditions, and protecting the developing baby from the harms associated with exposure to medicines or exposure to negative consequences of exacerbation of maternal conditions. To add complexity, pregnancy is associated with numerous physiological changes such as increases in plasma volume, cardiac output, liver metabolism, glomerular filtration rate and fat stores.4 These changes lead to changes in drug concentrations due to haemodilution and increased distribution, metabolism and excretion.4 This may render pregnant women more susceptible to medicines-related problems.

Is our perception of risk exaggerated?

Since the thalidomide experience in the 1960s there has been a reluctance to prescribe, or take, medicines in pregnancy because of fears of the potential teratogenic effects.5-7 Birth defects are a leading cause of infant mortality and obviously an important public health issue.7 Around 2–4% of babies are born with a birth defect,6 however, it has been estimated that only 1% of these birth defects  are caused by medicine use in pregnancy,6,7 even though most women will take some form of medicine while pregnant.2 The wide-spread belief that medicines are the cause of most birth defects may lead to health professionals giving overly cautious advice to pregnant women.5,6

Pitfalls of prescribing in pregnancy

While it may seem obvious that the safest solution is to avoid all medicines while pregnant, this stance has the potential to leave both the mother and the baby at risk of complications from untreated chronic conditions, or untreated conditions that emerge during pregnancy. For example, poorly controlled asthma is associated with poor pregnancy outcomes such as low birth weight, pre-term birth and pre-eclampsia.8,9 Is fear of prescribing harmful?

There is a perception that any exposure to medicines, or indeed any other chemical substances or infectious agents, is harmful to the developing baby.6,7,10 This fear of exposure may even result in unnecessary terminations.7,10 An Australian study looking at calls to MotherSafe, a NSW-based teratogen information service, found that of the 177 women who called between 2005 and 2007 who were considering a termination due to exposure, only around 30% had actually been exposed to a recognised teratogen.10

Additionally, fear of medicine use in pregnancy may prevent women from being adequately treated for existing illness during pregnancy. Chronic medical conditions are common in pregnancy. One Australian survey of pregnant women attending outpatient clinics at a large maternity hospital reported that around 40% had a chronic health problem such as asthma or diabetes.9 Of the women in this study with chronic disease who were regularly prescribed medicines, over half reported that they were not adherent.9 Many of the women also believed that complementary therapies were safer than other medicines during pregnancy, and around 7 in 10 women had taken vitamins, dietary minerals, or herbal or food supplements such as fish oil, Echinacea, arnica and glucosamine.9

Health professionals may withdraw or switch medicines during pregnancy because of fears of birth defects or other harms to the fetus. A survey of women taking psychoactive drugs found that most discontinued because of fears they would harm the baby, and most of these women had received advice from their doctor to do so.11 Around 70% of women in the survey reported adverse effects from stopping their medicines, 30% reported suicidal ideation.11 One of the concerns with health professional directed cessation of a medicine which is working, is the risk that women will self medicate with either complementary medicines5 or more harmful substances such as alcohol or illicit drugs.5,11 Indeed some women may even terminate an otherwise healthy pregnancy because of the relapsing symptoms of an underlying condition.11

Realistic guidance for medicines in pregnancy

Lack of information and evidence

Traditional sources of information such as Product Information and Consumer Medicines Information leaflets often lack information about use in pregnancy and often rely on animal data to investigate safety in pregnancy.10 Even the TGA categorisation of drugs in pregnancy has been criticised. In part, this is because there is a lack of evidence about the safe use of a particular medicine in pregnancy.

There is a risk that prescribers may ascribe excess risk to a particular medicine based on the TGA category rather than the quality of the evidence informing the category choice.5 The TGA category is meant as a guide only, but this may be interpreted as outright proof that a medicine is unsafe and not fully account for the clinical need in a particular patient.5 One of the main problems facing health professionals and regulatory bodies is the lack of good quality evidence of safety of medicines in pregnancy. The ethical barriers of administering medicines which may cause harm to a pregnant woman has resulted in little or no experimental evidence on safety in pregnancy.5 Most harmful medicines are identified through case studies, registries of exposure, post-marketing surveillance and sometimes through epidemiological investigation.6 However, this does little to help allay fears as messages can be confusing and information slow to filter.

For example, untreated depression has been shown to have negative consequences on maternal and fetal health and pregnancy outcomes,7 and discontinuation of antidepressants in pregnancy is associated with relapse.12 Recent evidence however, has also linked antidepressant use to poor birth outcomes (including low birth weights, increased pre-term births)13 which highlights the confusing messages which face health professionals. Is it possible that an overly cautious approach to medicines may be harming women with who are affected by medical conditions?

There are only a small number of drugs which have been unequivocally identified as human teratogens, such as retinoids, warfarin, anticonvulsants and thalidomide.6 However, even within known teratogens there are complex risk–benefit considerations that need to take place when deciding on medicines in pregnancy. For example, the Product Information for phenytoin sodium (a TGA category D medicine associated with negative pregnancy outcomes, such as craniofacial defects, oral clefts and cardiac abnormalities) states that the harms from uncontrolled epilepsy may be greater than the risk of taking phenytoin.14

Therapeutic Guidelines also recommends a careful balancing of risk from anti-epileptic medicines with the risk to the mother and baby of severe seizure.15 Other medicines may have unknown or potential adverse effects on the baby, but their benefits of use in a pregnant woman requiring treatment may still outweigh any potential harms.7 See Australian Prescriber for an editorial and review on the treatment of nausea and vomiting in pregnancy.

Rational approach to prescribing in pregnancy

"Optimal medicine use in pregnancy means the maintenance of good health outcomes for both the mother and the baby."7

Therapeutic Guidelines suggests the use of the following check list when deciding on whether to prescribe, or continue to prescribe, a particular medicine to pregnant women.15

Non-pharmacological treatment: Is such a treatment available and likely to be successful? Would such treatment be reasonable at least until the first trimester is complete? Most pregnant women strongly favour this type of treatment and compliance is likely to be high.

Harm–benefit analysis: For the particular drug under consideration, what are the potential harms and benefits to the mother and harms to the baby of prescribing? What are the harms and benefits (for each) of not prescribing?

Incidence of spontaneous congenital abnormality: When drugs cannot be avoided, it may be appropriate to discuss the incidence of non-drug–related, spontaneous abnormalities. This is often underestimated. The incidence in Australia of significant congenital abnormality is 2% to 4% of live births, and minor abnormalities are recognised in approximately 15% of newborns.

Education, documentation and communication: Has the education of the woman and her partner regarding harms and benefits been properly documented in the patient's notes? Have those health professionals involved in obstetric management been informed? It may be appropriate to discuss the use and limitations of available antenatal screening to detect abnormalities. Couples will need to give some consideration to the consequences of an abnormal result.

Routine review later in the pregnancy should include consideration of whether dose alteration is indicated during delivery to avoid neonatal problems such as respiratory depression.

Medicine choice

The Australian Medicines Handbook recommends that medicines that have been used for a long time with little evidence of associated birth defects or negative pregnancy outcomes should be chosen over newer medicines with less evidence about their safety in pregnancy.16 However, be aware that it might be inappropriate to switch a woman from a medicine that is working to a different one based solely on TGA category or length of time that the medicine has been in use.5

Sources of further information

For patients:

  1. Daw JR, Hanley GE, Greyson DL, et al. Prescription drug use during pregnancy in developed countries: a systematic review. Pharmacoepidemiol Drug Saf 2011;20:895–902. [Pubmed]
  2. Henry A, Crowther C. Patterns of medication use during and prior to pregnancy: the MAP study. Aust N Z J Obstet Gynaecol 2000;40:165–72. [Pubmed]
  3. Liew Z, Ritz B, Rebordosa C, et al. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr 2014. doi: 10.1001/jamapediatrics.2013.4914 [Pubmed]
  4. Stephens S, Wilson G. Prescribing in pregnant women: guide to general principles. Prescriber 2009;43–6. [Full text] (accessed 3 March 2014).
  5. Kennedy DS. A to X: the problem of categorisation of drugs in pregnancy-an Australian perspective. Med J Aust 2011;195:572–4. [Pubmed]
  6. Webster WS, Freeman JA. Is this drug safe in pregnancy? Reprod Toxicol 2001;15:619–29. [Pubmed]
  7. Hancock RL, Koren G, Einarson A, et al. The effectiveness of teratology information services (TIS). Reprod Toxicol 2007;23:125–32. [Pubmed]
  8. National Asthma Council Australia. Australian Asthma Handbook. 2014. [Online] (accessed 13 March 2014).
  9. Sawicki E, Stewart K, Wong S, et al. Medication use for chronic health conditions by pregnant women attending an Australian maternity hospital. Aust N Z J Obstet Gynaecol 2011;51:333–8. [Pubmed]
  10. Lim JM, Sullivan E, Kennedy D. MotherSafe: review of three years of counselling by an Australian teratology information service. Aust N Z J Obstet Gynaecol 2009;49:168–72. [Pubmed]
  11. Einarson A, Selby P, Koren G. Abrupt discontinuation of psychotropic drugs during pregnancy: fear of teratogenic risk and impact of counselling. J Psychiatry Neurosci 2001;26:44–8. [Pubmed]
  12. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006;295:499–507. [Pubmed]
  13. Huang H, Coleman S, Bridge JA, et al. A meta-analysis of the relationship between antidepressant use in pregnancy and the risk of preterm birth and low birth weight. Gen Hosp Psychiatry 2014;36:13–8. [Pubmed]
  14. Sandoz Pty Ltd. Product Information Phenytoin Sandoz. 2013. [Online] (accessed 13 March 2014).
  15. Therapeutic Guidelines Limited. eTG complete [internet]. Melbourne: 2013. [Online] (accessed 2 May 2013).
  16. Australian medicines handbook: prescribing in pregnant women. Adelaide: Australian Medicines Handbook Ltd, 2014